Project Summary/ Abstract Myasthenia Gravis (MG), which affects 60,000 people in the U.S., is an autoimmune disease caused by autoantibodies that attack the neuromuscular junction. For many MG patients, there is no safe, selective, and effective therapy, and MG remains a chronic, debilitating, and potentially fatal disease. Today, despite knowledge that the disease is mediated by autoantibodies produced by aberrant plasma cells (PCs), treatment of generalized MG still relies on indiscriminate immunosuppression with systemic steroids or steroid-sparing immunomodulators. Targeting a PC-restricted antigen would eliminate aberrant autoantibody-producing plasma cell clones, reduce pathogenic autoantibody, and could improve disease symptoms. One such target antigen is B-Cell Maturation Antigen (BCMA), which is expressed on all healthy PCs and on malignant PCs (i.e., multiple myeloma (MM)). Clinical trials with autologous anti-BCMA Chimeric Antigen Receptor (CAR) T-cells permanently modified by gene transfer show unprecedented efficacy in relapsed/refractory MM, but permanent genetic modification of T-cells leads to uncontrolled proliferation and unpredictable pharmacokinetics in vivo. The resulting toxicity can be severe and lethal. In order to preserve CAR T-cell efficacy but significantly reduce toxicity, Cartesian Therapeutics pioneered development of anti-BCMA CAR T-cells (named as Descartes-08) with defined, controllable pharmacokinetics by transfecting T-cells with CAR mRNA instead of by gene transfer. This project is intended to determine the feasibility of treating generalized MG with mRNA-transfected CAR T- cells. The hypothesis to be tested is that dosing Descartes-08 at or below the maximal tolerated dose (MTD) will achieve a high rate of clinical remission in patients with severe generalized MG.